1-(4-Methoxyphenyl)-3-(3-phenoxyphenyl) prop-2-en-1-one: A Diphenyl Chalcone Derivative with Potent Antitumor Activity Via Up-Regulation of p21 Gene

Background and Aim: Cancer is a disease of complex aetiology and is characterised by uncontrolled growth of abnormal cells. It is a major worldwide health problem. Many natural and synthetic chalcone or their derivatives showed anticancer activities. The aim of the present study is to evaluate the anticancer activity of novel chalcone derivatives and also to establish possible mechanism of action. Materials and Methods: A series of chalcones 3-(3-phenoxyphenyl)-1-phenylprop-2-en-1-one (2a); 1-(4-chlorophenyl)-3-(3-phenoxyphenyl) prop-2-en-1-one (2b); 1-(4-fluorophenyl)-3-(3-phenoxyphenyl) prop-2-en-1-one (2c); 1-(4-Nitro-phenyl)-3-(3-phenoxy-phenyl)prop-2-en-1-one (2d); 1-(4-methoxyphenyl)-3-(3-phenoxyphenyl) prop-2-en-1-one(2e) were evaluated for the cytotoxic activity both in vitro and in vivo. The in vivo antitumor activity of these compounds was estimated on Daltons Ascites Lymphoma induced solid tumor model. The effect of promising compound was further analysed by flow cytometer and RT- PCR analysis. Results and Conclusion: 1-(4-methoxyphenyl)-3-(3-phenoxyphenyl) prop-2-en-1-one and 1-(4- chlorophenyl)-3-(3-phenoxyphenyl) prop-2-en-1-one was showed in vitro cytotoxic activity, DNA damage and antiproliferative activity. DLA induced solid tumor model suggested that 1-(4-methoxyphenyl)-3-(3- phenoxy phenyl) prop-2-en-1-one significantly reduced the tumor volume, increase the percentage tumor inhibition and reverse the haematological parameters. Flow cytometry analysis concluded that the compound induces cell cycle arrest at G0/G1 phase due to the over expression of p21. 1-(4-methoxyphenyl)-3-(3- phenoxy phenyl) prop-2-en-1-one may be a potential agent for cancer treatment.

589 Enhancement of the anti-tumor effects of CD47 blockade in solid tumors by combination with targeted radioimmunotherapy

BackgroundOne mechanism that tumors use to escape immunosurveillance is the overexpression of CD47, which inhibits the macrophage mediated phagocytosis pathway. Although blockade of the CD47-SIRPα axis is a promising approach to enhance tumor targeted phagocytosis, anti-CD47 monotherapies have not shown meaningful responses in clinical studies of solid tumors. Combination cancer therapies aim to increase the probability of response in settings of resistance by combining drugs with different mechanisms of action. Antibody radioconjugates (ARCs) specifically target and deliver therapeutic radiation directly to cancer cells. We rationalized that the immunogenic and cytotoxic properties of ARCs will upregulate calreticulin (CRT), a pro-phagocytic signal, thereby synergizing with CD47 blocking therapies to enhance phagocytosis and antitumor activity. Here for the first time, we demonstrate the combination benefit of a HER2 specific targeting ARC and a CD47 blocking antibody to enhance therapeutic efficacy in preclinical solid tumor models.MethodsThe anti-HER2 antibody trastuzumab was conjugated with p-SCN-DOTA and radiolabeled with Ac-225 or Lu-177. The biological activity of both radioconjugates was evaluated using human recombinant HER2 and receptor positive tumor cell lines. The cytotoxic effect of radioconjugates and the ability to upregulate CRT was evaluated using XTT assay and flow cytometry, respectively, in a panel of HER2 expressing cells. To evaluate the synergy of anti-HER2 ARC and CD47 antibody combination in vitro, a flow cytometry macrophage phagocytosis assay was developed. We further evaluated the antitumor synergy in vivo between anti-HER2 ARC and CD47 antibody in human HER2 positive tumor xenograft mouse model.ResultsThe anti-HER2 ARCs have similar binding properties to native antibody and demonstrate specific cytotoxicity. Importantly, we observe ARC-mediated CRT upregulation in HER2 expressing cells. Furthermore, the combination of HER2 targeting ARC and CD47 blocking antibody enhances in vitro macrophage mediated tumor cell phagocytosis compared to each agent alone. Remarkably, the in vivo anti-HER2 ARC and CD47 antibody combination shows enhanced therapeutic effect with reduced toxicity and improved survival benefit in a human preclinical solid tumor model.ConclusionsHere for the first time, we demonstrate enhanced therapeutic efficacy between an anti-HER2 ARC and CD47 blocking antibody combination in a preclinical solid tumor model. The finding suggests that ARC mediated upregulation of CRT potentiates the pro-phagocytic signal and synergizes with the anti-CD47 mode of action thereby enhancing antitumor immune response. This combination mechanism provides a very promising strategy to improve therapeutic responses in patients harboring solid tumors and warrants further preclinical evaluation.Ethics ApprovalAll animal experiments were approved by IACUC.

Baicalein exerts antitumor effect in cervical cancer

The work verified that baicalein (BCN) inhibited the appearance and progress of cervical cancer in vitro and in vivo. MTT and CCK-8 methods were used to detect the toxicity of BCN to C33A cells and the number of C33A cells, respectively. For in vivo assays, a solid tumor model of cervical cancer and ascites tumor model was successfully established. The body weight, tumor volume and weight, survival time, and ascites volume were recorded. The anti-tumor ratio and increasing rate of life span were computed. H&E staining was performed to examine the liver tissues, kidney tissues, and tumor tissues. BCN inhibits the proliferation of human cervical cancer cell line C33A and induces apoptosis. The results from in vivo assays showed that BCN suppressed tumor growth and progression with decreased tumor volume and weight in a solid tumor model. BCN significantly induced cell apoptosis in solid tumor tissues. BCN also reduced ascites volume, prolonged survival time, and increased life extension rate in the ascites tumor model. These findings indicated that BCN exerted an antitumor effect against cervical cancer both in vitro and in vivo. According to the results, BCN might act as an important antitumor agent against cervical cancer.

Gold nanoparticle transport in multilayered cell cultures

Gold nanoparticles (GNPs) possess a number of useful characteristics that have catapulted them into the mainstream of cancer research. Their optical properties enable them to be used in photodynamic and photothermal therapy as well as contrast agents in photoacoustic imaging. In addition, the ability to bind ligands to the GNP surface has made them valuable bio-markeraware drug carriers. But the effectiveness of any cancer fighting tool relies on homogenous distribution and penetration throughout the tumor, and the uptake and transport dynamics of GNPs has previously been held to monolayer cell models. In this work, multicellular layers (MCLs) are used as a solid tumor model to measure the penetration and uptake of GNPs in tumor tissue. MCLs offer a unique way to bridge the gap between in vitro single-layer cell models and the in vivo tumor. The effects of increased cell-to-cell connections, extracellular matrix and tumor characteristics are investigated to deliver new insights into the transport of GNPs in tissue.

Gold nanoparticle transport in multilayered cell cultures

Gold nanoparticles (GNPs) possess a number of useful characteristics that have catapulted them into the mainstream of cancer research. Their optical properties enable them to be used in photodynamic and photothermal therapy as well as contrast agents in photoacoustic imaging. In addition, the ability to bind ligands to the GNP surface has made them valuable bio-markeraware drug carriers. But the effectiveness of any cancer fighting tool relies on homogenous distribution and penetration throughout the tumor, and the uptake and transport dynamics of GNPs has previously been held to monolayer cell models. In this work, multicellular layers (MCLs) are used as a solid tumor model to measure the penetration and uptake of GNPs in tumor tissue. MCLs offer a unique way to bridge the gap between in vitro single-layer cell models and the in vivo tumor. The effects of increased cell-to-cell connections, extracellular matrix and tumor characteristics are investigated to deliver new insights into the transport of GNPs in tissue.

Head-To-Head Comparison of Biological Behavior of Biocompatible Polymers Poly(Ethylene Oxide), Poly(2-Ethyl-2-Oxazoline) and Poly[N-(2-Hydroxypropyl)Methacrylamide] as Coating Materials for Hydroxyapatite Nanoparticles in Animal Solid Tumor Model

Nanoparticles (NPs) represent an emerging platform for diagnosis and treatment of various diseases such as cancer, where they can take advantage of enhanced permeability and retention (EPR) effect for solid tumor accumulation. To improve their colloidal stability, prolong their blood circulation time and avoid premature entrapment into reticuloendothelial system, coating with hydrophilic biocompatible polymers is often essential. Most studies, however, employ just one type of coating polymer. The main purpose of this study is to head-to-head compare biological behavior of three leading polymers commonly used as “stealth” coating materials for biocompatibilization of NPs poly(ethylene oxide), poly(2-ethyl-2-oxazoline) and poly[N-(2-hydroxypropyl)methacrylamide] in an in vivo animal solid tumor model. We used radiolabeled biodegradable hydroxyapatite NPs as a model nanoparticle core within this study and we anchored the polymers to the NPs core by hydroxybisphosphonate end groups. The general suitability of polymers for coating of NPs intended for solid tumor accumulation is that poly(2-ethyl-2-oxazoline) and poly(ethylene oxide) gave comparably similar very good results, while poly[N-(2-hydroxypropyl)methacrylamide] was significantly worse. We did not observe a strong effect of molecular weight of the coating polymers on tumor and organ accumulation, blood circulation time, biodistribution and biodegradation of the NPs.